Cytomegalovirus Encephalitis Research Articles

Cytomegalovirus Treatment in Solid Organ Transplantation: An Update on Current Approaches.

The article reviews the safety and efficacy of treatments for cytomegalovirus (CMV) in solid organ transplantation. A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from database inception through January 2024, using terms CMV, therapy, and solid organ transplantation. Clinical trials, meta-analyses, cohort studies, case reports, and guidelines were included. Letters to the editor, reviews, and commentaries were excluded. After abstract screening and full-text review of 728 citations for eligibility, 53 were included. Valganciclovir and intravenous ganciclovir are drugs of choice for CMV management and, until recently, the availability of alternative options has been restricted due to toxicity. For instance, foscarnet and cidofovir serve as second-line agents due to potential bone marrow and renal toxicity. In patients with refractory or resistant CMV, maribavir, a novel oral agent, has proven efficacy and a lower adverse effect profile. However, in refractory or resistant CMV, foscarnet and cidofovir are preferred in invasive disease (CMV gastritis, CMV retinitis, and CMV encephalitis), high viral loads, and inability to tolerate oral preparations. Consensus guidelines have not been revised since approval of novel antivirals in solid organ transplantation. Valganciclovir and ganciclovir remain drugs of choice for initial CMV therapy. Foscarnet, cidofovir, and maribavir are treatments for refractory or resistant-CMV. Selection of CMV antiviral treatment should be determined by patient-specific factors, including severity of illness, resistant or refractory disease, dose-limiting adverse effects, and the preferred route of administration.

Nanopore targeted sequencing-based diagnosis of central nervous system infections in HIV-infected patients

BackgroundEarly and accurate etiological diagnosis is very important for improving the prognosis of central nervous system (CNS) infections in human immunodeficiency virus (HIV)-infected patients. The goal is not easily achieved by conventional microbiological tests. We developed a nanopore targeted sequencing (NTS) platform and evaluated the diagnostic performance for CNS infections in HIV-infected patients, with special focus on cryptococcal meningitis (CM). We compared the CM diagnostic performance of NTS with conventional methods and cryptococcal polymerase chain reaction (PCR).MethodsThis study included 57 hospitalized HIV-infected patients with suspected CNS infections from September 2018 to March 2022. The diagnosis established during hospitalization includes 27 cases of CM, 13 CNS tuberculosis, 5 toxoplasma encephalitis, 2 cytomegalovirus (CMV) encephalitis and 1 Varicella-zoster virus (VZV) encephalitis. The 2 cases of CMV encephalitis also have co-existing CM. Target-specific PCR amplification was used to enrich pathogen sequences before nanopore sequencing. NTS was performed on stored cerebrospinal fluid (CSF) samples and the results were compared with the diagnosis during hospitalization.Results53 (93.0%) of the patients were male. The median CD4 cell count was 25.0 (IQR: 14.0–63.0) cells/uL. The sensitivities of CSF culture, India ink staining, cryptococcal PCR and NTS for CM were 70.4% (95%CI: 51.5 − 84.1%), 76.0% (95%CI: 56.6 − 88.5%), 77.8% (59.2 − 89.4%) and 85.2% (95%CI: 67.5 − 94.1%), respectively. All those methods had 100% specificity for CM. Our NTS platform could identify Cryptococcus at species level. Moreover, NTS was also able to identify all the 5 cases of toxoplasma encephalitis, 2 cases of CMV encephalitis and 1 VZV encephalitis. However, only 1 of 13 CNS tuberculosis cases was diagnosed by NTS, and so did Xpert MTB/RIF assay.ConclusionsNTS has a good diagnostic performance for CM in HIV-infected patients and may have the ability of simultaneously detecting other pathogens, including mixed infections. With continuing improving of the NTS platform, it may be a promising alterative microbiological test for assisting with the diagnosis of CNS infections.

Extranodal involvement of posttransplant lymphoproliferative disorder detected on 18F‐fluorodeoxyglucose‐positron emission tomography/computed tomography

A 69-year-old man with a history of kidney transplantation presented with ring-enhancing lesions in the left frontal lobe, thalamus, and right insula (Figure 1a) on magnetic resonance imaging. He was hospitalized with a diagnosis of cytomegalovirus encephalitis and had taken anti-inflammatory therapy. Follow up imaging showed a decrease in lesion size in the left frontal lobe and thalamus; however, the right insular lesion increased in size and new ones were identified in the corpus callosum and periventricular white matter (Figure 1a). The tumor markers CA125, CYFRA21-1, CEA, PSA, and fPSA were all positive on blood testing. Because anti-inflammatory therapy was ineffective and malignant tumor could not be excluded on imaging alone, whole-body 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) was performed (Figure 1b). Body imaging showed multiple hypermetabolic nodular lesions in the thoracic and abdominal superficial soft tissue (maximum standardized uptake value, 13.06), which suggested malignancy. Head imaging showed decreased activity in the brain lesions. A diagnosis of lymphoma was suspected. Punch biopsy of a superficial soft tissue nodule was consistent with B cell-derived posttransplant lymphoproliferative disorder (PTLD) (Figure 1c,d). Brain MRI, 18F-FDG PET, and histopathological findings in a 69-year-old male patient with posttransplant lymphoproliferative disorder. (a) Abnormal signals in T2-flair MRI images within 3 months (solid arrow). (b) 18F-FDG PET/CT images show multiple lesions in superficial soft tissue nodules with hypermetabolism and decreased FDG activity of intracranial lesions (solid arrow). (c) Immunohistochemical staining shows positive CD3. (d) Immunohistochemical staining shows enlarged B cells (solid arrow). 18F-FDG, 18F-fluorodeoxyglucose; CT, computed tomography; PET, positron emission tomography. PTLD is a rare group of heterogeneous lymphoproliferative conditions that occur after solid organ or hematopoietic transplantation [1, 2]. With allograft transplantation, the anatomic site of PTLD involvement usually depends on the type of transplant [3]. Reported incidence rates of involvement of the central nervous system range between 10% and 15% [4, 5]. However, simultaneous involvement of the central nervous system [6] and superficial soft tissue [7] are rare. To date, only two cases of PTLD soft tissue nodules have been reported [4]. Characteristics of PTLD on magnetic resonance imaging are not specific; however, PTLD can be detected on 18F-FDG-PET with an overall sensitivity and specificity of approximately 90% [8, 9]. PTLD should be considered when multiple hypermetabolic superficial soft tissue nodules and central nervous system lesions are encountered in transplantation patients. Whole-body18F-FDG-PET/CT is more effective than single-site imaging for diagnosing or staging PTLD. Bojun Wang: Data curation (lead); Writing – original draft (lead). Tianbin Song: Conceptualization (equal); Writing – review & editing (equal). Chun Zhang: Conceptualization (equal); Supervision (equal). Jie Lu: Supervision (equal). Zhigang Liang: Supervision (equal); Writing – review & editing (equal). We thank Dr. Lianghong Teng (Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China) who provided support of pathological picture of this case. All the authors declare that they have no conflict or potential conflict of interest. This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from the patient and his parents for the anonymous use of his clinical, imaging, and histologic data for publication. The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Familial CD45RA- T cells to treat severe refractory infections in immunocompromised patients.

Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. Most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. The transfer of pathogen-specific Cytotoxic T-Lymphocytes has shown a minimal toxicity profile and effectiveness in treating Cytomegalovirus, Adenovirus, Epstein - Barr virus, BK Virus and Aspergillus infections, but this therapy have the main limitations of regulatory issues, high cost, and absence of public cell banks. However, CD45RA- cells containing pathogen-specific memory T-cells involve a less complex manufacturing and regulatory process and are cheaper, feasible, safe, and potentially effective. We present preliminary data from six immunocompromised patients: four who had severe infectious diseases and two who had EBV lymphoproliferative disease. All of them underwent multiple safe familial CD45RA- T-cell infusions as adoptive passive cell therapy, containing Cytomegalovirus, Epstein - Barr virus, BK virus, and Aspergillus-specific memory T-cells. We also present the method for selecting the best donors for CD45RA- cells in each case and the procedure to isolate and store these cells. The infusions were safe, there was no case of graft-versus host disease, and they showed a clear clinical benefit. The patients treated for BK virus nephritis, Cytomegalovirus encephalitis, Cytomegalovirus reactivation, and disseminated invasive aspergillosis experienced pathogen clearance, complete resolution of symptoms in 4-6 weeks and a lymphocyte increase in 3 of 4 cases after 3-4 months. Donor T cell transient microchimerism was detected in one patient. The two patients treated for EBV lymphoproliferative disease underwent chemotherapy and several infusions of CD45RA- memory T-cells containing EBV cytotoxic lymphocytes. Donor T-cell microchimerism was observed in both patients. The viremia cleared in one of the patients, and in the other, despite the viremia not clearing, hepatic lymphoproliferative disease remained stable and was ultimately cured with EBV-specific Cytotoxic T-Lymphocytes. The use of familial CD45RA- T-cells containing specific Cytotoxic T-lymphocytes is a feasible, safe and potential effective approach for treating severe pathogen infections in immunocompromised patients through a third party donor. Furthermore, this approach might be of universal use with fewer institutional and regulatory barriers.

Corrigendum: AIDS-related cytomegalovirus encephalitis in the late ART era: A retrospective cohort study at a referral center in Brazil

Corrigendum: AIDS-related cytomegalovirus encephalitis in the late ART era: A retrospective cohort study at a referral center in Brazil

Uncommon histopathological features of cytomegalovirus encephalitis and measles inclusion body encephalitis on autopsy in two patients with primary immunodeficiency.

To describe the neuropathological findings in two patients with primary immunodeficiency who had fatal viral encephalitis. Severe combined immunodeficiency (SCID) was confirmed in case 1 by genetic testing, while case 2 had features suggestive of combined immunodeficiency; however, whole exome sequencing showed no pathogenic variants. Autopsies were performed in both cases after an informed consent. A detailed sampling of the brain including extracranial organs was conducted. Immunohistochemistry and electron microscopy was also performed to confirm the presence of viruses. Besides evidence of cystic encephalomalacia observed in both cases, the brain in case 1 revealed cytomegalovirus (CMV) ventriculoencephalitis accompanied by an exuberant gemistocytic response in the entire white matter. Nuclei of gemistocytes were loaded with several CMV nuclear inclusions, which was confirmed by immunohistochemistry. Case 2 demonstrated features of measles inclusion body encephalitis with several viral inclusions within neurons and astrocytes. Rare giant cells were also seen. Measles virus was confirmed on immunohistochemistry and electron microscopy. Plausibly, there was paucity of microglial nodules in both cases. Superadded bacterial pneumonia with diffuse alveolar damage was also seen in both cases. These cases add to the spectrum of unusual histological features of viral encephalitis seen in patients with underlying primary immunodeficiency diseases.

AIDS-related cytomegalovirus encephalitis in the late ART era: A retrospective cohort study at a referral center in Brazil.

AIDS-related cytomegalovirus (CMV) encephalitis has declined in the combined antiretroviral therapy (ART) era in high-income countries. However, there is scarce information on CMV encephalitis in low- and middle-income countries. The objectives of this study were to identify the prevalence of AIDS-related CMV encephalitis and describe its main features. This was a retrospective cohort study carried out at a referral center in São Paulo, Brazil. We included adult people living with HIV/AIDS (PLWHA), hospitalized in 2019, with a CD4 cell count ≤100/mm3 and quantitation CMV DNA results in plasma. Cases with compatible neurological manifestations and detection of CMV DNA by polymerase chain reaction (PCR) in cerebrospinal fluid samples were defined as CMV encephalitis. Among 761 PLWHA hospitalized, 248 (32.5%) cases were included in this study. Prevalence of CMV encephalitis was 2.4% (6/248) among all included cases and 7.7% (6/78) among individuals with neurological opportunistic diseases. The six patients with CMV encephalitis were males and had CD4 cell count <50/mm3. Five (83%) cases had CMV encephalitis as AIDS-defining disease and showed CMV DNA detection by PCR >50,000UI/mL plasma. All six cases received anti-CMV therapy (ganciclovir, n = 4; ganciclovir plus foscarnet, n = 2) and five were discharged to home. CMV encephalitis was not uncommon among hospitalized PLWHA with neurological opportunistic diseases. The epidemiological and immunological profile of individuals with CMV encephalitis was similar to that described in the pre-ART era, but in contrast, most cases were treated and discharged from the hospital.

Updated efficacy and safety report of a phase I trial of donor-derived CD7 CAR T cells for T-cell acute lymphoblastic leukemia.

7023 Background: Results of a phase I trial of donor-derived CD7 chimeric antigen receptor (CAR) T cells for relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) (Pan et al. J Clin Oncol 2021;39:3340-3351) have been reported previously, and are updated now. Methods: The target dose is 1 × 106 (±30%) CAR T cells per kg of body weight. Patients with prior stem cell transplantation (SCT) received CAR T cells from prior SCT donors, while patients without SCT history received CAR T cells from new donors who also provided stem cells for transplantation post CAR T therapy. The primary endpoint was safety with efficacy secondary. Survival status were continuously followed up while severe adverse events (SAEs) were recorded until receiving other anti-leukemia therapy. Results: Nineteen (95%) of twenty enrolled patients responded and were followed up with a median time of 15.8 months (range 13-18.3) until Feb, 14th, 2022. Short-term adverse events included grade 3 or higher cytokine release syndrome (10%) and grade 1-2 graft-versus-host disease (GVHD, 60%), which were all reversible. Six late-onset ( &gt; 30 days post-infusion) severe adverse events (SAEs) occurred in 5 responders. Two had been reported previously. Four SAEs were newly observed, including a grade 4 intestinal GVHD at month 11 and a grade 5 pneumonia at month 12.3 in one patient, a grade 5 Pseudomonas Aeruginosa pneumonia at month 8.7 in one patient, and a grade 3 cytomegalovirus (CMV) encephalitis at month 11 which recovered at month 13.3 in another patient. All severe infections occurred in patients with no further therapy, and the total T cells in them reached a median count of 300.03/μL (range 121.46-512.83), which were substantially lower than normal levels despite steadily increasing. The objective response and complete remission rate was 95% and 85% at day 30 post-infusion. Of 19 responders that were followed up, two (11%) withdrew for other therapy at day 55 and 271 respectively. Of 10 (53%) patients who received no further therapy, all had continuously detectable CAR T cells until the last visit, three remained in remission, three had a relapse (one CD7+, and two CD7-), and four died of infection; Seven (37%) patients proceeded to SCT and no CAR T cells were detectable after SCT, and among them two remained in remission, four had a relapse (three CD7+, and one CD7-), and one died of transplant-related mortality. Patients relapsed at a median time of 6 (range 4-10.9) months. The one-year progressive-free survival (PFS) and overall survival (OS) rates were 51.6% (95% CI, 24.7-78.4%) and 72.5% (95% CI, 51.9-93.0%). Conclusions: Donor-derived CD7 CAR T cell therapy showed encouraging activity in treating r/r T-ALL. Relapse emerges as major issues impeding long-term outcomes. CD7-negative relapse was commonly observed under CAR T cell surveillance. Late onset GVHD and infections may occur and should be carefully managed. Clinical trial information: ChiCTR2000034762.

Vascular inflammation in the central nervous system.

Vascular inflammation in the central nervous system.

Phase II Study of Venetoclax in Combination with Obinutuzumab and Bendamustine in Patients with High Tumor Burden Follicular Lymphoma As Front Line Therapy (PrECOG 0403)

Phase II Study of Venetoclax in Combination with Obinutuzumab and Bendamustine in Patients with High Tumor Burden Follicular Lymphoma As Front Line Therapy (PrECOG 0403)

Suspected Central Nervous System Infections in HIV-Infected Adults.

Objectives: To study the differential diagnosis of HIV-infected patients with suspected central nervous system (CNS) infections and the association of CD4 counts with the final diagnosis.Methods: We analyzed HIV-infected patients from a prospective cohort study on the diagnostic accuracy of clinical and laboratory characteristics in adults with suspected CNS infections in an academic hospital in Amsterdam, the Netherlands, who underwent cerebrospinal fluid (CSF) examination.Results: Thirty-four (9.4%) out of 363 patients with suspected CNS infections were HIV-positive of whom 18 (53%) were diagnosed to have CNS infection, with median CD4 counts of 255 cells/μl. The spectrum of CNS infections consisted of progressive multifocal leukoencephalopathy in three patients (17%); cryptococcal meningoencephalitis, toxoplasma encephalitis, angiostrongylus eosinophilic meningitis, and HIV encephalitis each in two (11%); and cytomegalovirus encephalitis, neurosyphilis, tuberculous meningoencephalitis, histoplasma encephalitis, and varicella-zoster virus meningitis each in one (6%). Clinical characteristics and blood parameters did not differ between HIV-infected patients with CNS infections and other diagnoses. The best predictor for CNS infections was the CSF leukocyte count (AUC = 0.77, 95 CI% 0.61–0.94). The diagnosis of CNS infection was not associated with the CD4 count (median 205 vs. 370, p = 0.21). Two patients (11%) with CNS infections died and two (11%) had neurological sequelae.Conclusions: Half of the patients with suspected CNS infections are diagnosed with a CNS infection, and this was not related to CD4 counts. The best predictor for CNS infections was the CSF leukocyte count.

Cytomegalovirus Encephalitis with Decreased Vision in Immunocompromised Patients Treated with Valganciclovir: Case Report

Introduction: Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in patients with Acquired Immune Deficiency Syndrome (AIDS). Almost all Human Immunodeficiency Virus (HIV) infected patients develop CMV rapidly with manifestation in the central nervous system. Most CMV encephalitis is preceded by the presence of CMV in other places. Therefore, immediate therapy will be more effective and the delay in therapy can be detrimental. Case: A 40-year-old man with the major complaint of vision decrease in both eyes for 3 months claimed that he felt worse after 7 days, accompanied by headache and fever. This patient was diagnosed with HIV 2 years ago. The examination obtained GCS 456, negative meningeal sign, headache with NRS 7. The visual acuity of the right eye was negative light perception and in the left eye of vision 1/300. The patient experienced clinical improvement after oral Valganciclovir therapy with a dose of 2x450 mg. Conclusion: CMV encephalitis must be considered to diagnose earlier in HIV patients with complaints of decreased vision. With valganciclovir 2x450 mg tablets improve reduction of headache scale NRS from 7 to 2, increasing left eye vision from 1/300 to 6/60. Keywords: Encephalitis CMV, HIV, Valganciclovir.

Distinguishing cytomegalovirus meningoencephalitis from other viral central nervous system infections.

Hallmarks of cytomegalovirus (CMV) meningoencephalitis include fever, altered mental status, or meningismus with pleocytosis, elevated protein and hypoglycorrhachia on cerebrospinal fluid (CSF) analysis. Magnetic resonance imaging may show ventriculitis, ependymitis or periventricular enhancement. Studies are limited comparing clinical and laboratory characteristics to other viral etiologies. This multi-center, retrospective cohort analysis reviewed patients with CMV meningitis or encephalitis and compared clinical features, laboratory findings and outcomes to the most common viral causes of meningoencephalitis. Patients with encephalitis or aseptic meningitis and detectable genetic material by polymerase chain reaction were identified. Clinical characteristics, laboratory findings and neuroimaging were collected from the electronic medical record. Data analysis was performed comparing CMV to other viral etiologies. 485 patients were evaluated and included cases of CMV (n=36) which were compared with herpes simplex virus (n=114), enterovirus (n=207), varicella zoster virus (n=41) and West Nile virus (n=81). Human immunodeficiency virus (HIV) infection was seen more frequently in CMV infection compared with all other viral etiologies. Clinical presentations and CSF findings of other viral etiologies differ compared with CMV. Hypoglycorrhacia occurred more often with CMV compared with other viral pathogens. Outcomes were significantly worse compared with enterovirus, herpes simplex virus and varicella zoster virus but not West Nile virus. CMV meningoencephalitis occurs most often in patients with HIV and encephalitis occurs more frequently than meningitis. Clinical and laboratory findings differ compared with other viral etiologies and can support consideration of CMV in the differential diagnosis of patients with meningoencephalitis.

Adoptive Immunotherapy with Rapidly-Generated Multivirus-Specific T Cells Against AdV, EBV, CMV, HHV6 and BK after Allogeneic Hematopoietic Stem Cell Transplant

Viral infections remain a significant cause of morbidity and mortality after allogeneic stem cell transplantation (HSCT). We now report on the outcomes of 67 patients infused with either donor-derived (n=21) or third party “off the shelf” (n=46) virus-specific T cells (VSTs) with activity against 5 common post-transplant viruses (EBV, CMV, Adv, BK, HHV6).We generated 84 clinical-grade VST lines by stimulating 30x106 PBMCs with overlapping peptide libraries spanning Adv (Hexon, Penton), CMV (pp65, IE1), EBV (LMP2, EBNA1, BZLF1), BKV (Large T, VP1) and HHV6 (U11, U14, U90) antigens. After a 9-11 day expansion phase in a G-Rex device in the presence of activating cytokines, a mean of 399x106 T cells (range 89-1006x106) were harvested. The lines were polyclonal, comprising both CD4+ (60±2%) and CD8+ (31±2%) cells and expressed central CD45RO+/CD62L+/CCR7+ (38±3%) and effector memory markers CD45RO+/CD62L-/CCR7- (10±1%). VST specificity was dependent on the donor's prior exposure to viruses; thus, 81/84 lines had activity against Adv (Hexon: 384±44; Penton: 293±50 SFC/2x105), 50/84 against CMV (IE1: 294±52; pp65 1009±194), 66/84 against EBV (LMP2: 153±26; EBNA1: 132±17; BZLF1: 91±25), 53/84 against BK (Large T: 134±22; VP1: 158±29) and 57/84 against HHV-6 (U90: 111±25; U14: 94±13; U11: 46±8).Twenty one allogeneic HSCT recipients were infused with donor-derived VSTs in a dose escalation study with informed consent; 4 on DL1 (5x106/m2), 4 on DL2 (1x107/m2) and 13 on DL3 (2x107/m2). Four patients received the cells prophylactically and remained free of viral infections up to 3 months post-infusion. The remaining patients were infused for one or more active infections. There were 4 cases of Grade I-II GvHD, of which only one required treatment with steroids. Based on viral load measurements and symptom assessment a single VST infusion successfully controlled active infections associated with all our targeted viruses (ORR 95%): CMV (7 CR, 1PR); EBV (7 CR, 1PR); Adv (6 CR); HHV6 (5 CR, 1PR, 1NR) and BKV (8 CR, 2 PR, 1 NR). Overall, we used VSTs to treat 7 cases of viral disease- EBV-PTLD (n=1), HHV-6 encephalitis (n=1), BKV hemorrhagic cystitis (HC) (n=5). The infused cells successfully cleared the EBV-PTLD (without rituximab) and HHV6 encephalitis, while all patients with BKV HC had marked improvement or resolution of symptoms post-VSTs.Based on the safety and efficacy profile of VSTs we extended our approach to third party recipients. To date we have treated 46 patients, all of whom had drug-refractory infections. Patients received 1-3 doses (fixed dose - 2x107 cells/m2) with 3rd party VSTs matching at one to six of eight HLA alleles. Despite the HLA disparity the cells have proven safe with three cases of de novo grade I-II GvHD documented. Third party VSTs successfully controlled active infections in 42 of 45 evaluable patients (ORR 94%): CMV (13 CR, 5 PR, 1 NR); EBV (2 CR); AdV (7 CR, 2 NR); BKV (5 CR, 14 PR); and HHV-6 (4 PR). Of note, 30 of 46 patients were treated for viral disease - CMV colitis (n=3), CMV encephalitis (n=1), EBV-PTLD (n=1), AdV respiratory tract infection (RTI) (n=2), AdV RTI and enteritis (n=1), AdV HC (n=1), HHV-6 encephalitis (n=2), BKV HC (n=17), BKV nephritis (n=2). All patients with BK-HC, 2 of 3 patients with CMV colitis, and the patients with CMV encephalitis, AdV RTI, enteritis and HC, and HHV-6 encephalitis had marked improvement or resolution of symptoms within 6 weeks following VST treatment. In more than 50% of responders (n=24) we detected an increase in the circulating frequency of VSTs post-infusion, which were confirmed to be 3rd party VST origin in 14 and remained detectable for up to 12 weeks post-infusion.Overall our experience with adoptively-transferred VSTs demonstrates not only the safety profile of the cells, even when administered as a 3rd party product, but also the efficacy of the infused cells in patients with up to 4 simultaneous/sequential infections, and HSCT recipients with virus associated disease. DisclosuresTzannou:ViraCyte LLC: Consultancy. Lulla:ASBMT Young Investigator Award: Research Funding; ASH Scholar Award: Research Funding; Leukemia Texas Research grant: Research Funding; Junior Faculty sees funding-Baylor College of Medicine: Research Funding; Lymphoma SPORE: Research Funding; Leukemia Texas: Membership on an entity's Board of Directors or advisory committees. Vera:Marker Therapeutics: Equity Ownership; ViraCyte LLC: Equity Ownership; Wilson Wolf Manufacturing: Consultancy. Rooney:ViraCyte LLC: Membership on an entity's Board of Directors or advisory committees. Heslop:Cell Medica: Patents & Royalties: EBV specific T cells, Research Funding; Viracyte: Equity Ownership; Marker Therapeutics: Equity Ownership; Celgene: Research Funding. Leen:ViraCyte LLC: Equity Ownership.

MO225CMV ENCEPHALITIS IN A SLE FLARE

Abstract Background and Aims Cytomegalovirus (CMV) infection is an opportunistic pathogen in immunocompromised patients and its management is well described after solid organ/bone marrow transplant or in HIV patients. Although less common, since Systemic Lupus Erythemathous (SLE) is a chronic auto immune disease often requiring intense immunosuppression to induce remission of disease exacerbation, SLE patients are also prone to it. Besides complicating the course of the disease, it may be a life-threatening infection. Due to the heterogeneity of SLE manifestations, usually is difficult to distinguish between a SLE flare and CMV active infection, making the diagnose challenging. It has also been described in the literature as an exacerbating SLE factor. We report the case of an Asian, 27-year-old woman, with a recent SLE diagnosis that was admitted with a SLE flare while developing a CMV encephalitis. She was previously admitted due to a nephrotic syndrome. Immunological studies revealed an ANA title of 1:640 and a positive anti dsDNA Ab with diminished C3 and C4 levels, nephrotic range proteinuria and a diagnose of SLE was made. Renal biopsy revealed class IV lupus nephritis. She started high dose intravenous methylprednisolone (3 pulses of 500mg) and mycophenolate mofetil (MMF) at a dose of 2g per day. She was discharged taking 60 mg of oral prednisolone and the same dose of MMF. Two weeks after being discharged, she was readmitted due to worsening anaemia (Hb 6.8 g/dL), thrombocytopenia (Pl 27 000/µL) and deteriorating renal function with a sCr of 5.5 mg/dL with de novo haematuria. It was admitted a severe SLE flare and she was given another 3 pulses of 500mg I.V methylprednisolone and cyclophosphamide (CYC) was started (1 pulse of 500mg I.V). At the same time, she started to complain of myalgias and malaise, generalized hypotonia, developed fever, leukopenia with neutropenia and seizures. Serum CMV viremia was 71 000 copies and CMV polymerase chain reaction was positive in cerebrospinal fluid. She was started on I.V Ganciclovir, CYC was suspended and clinical improvement was observed. Conclusion Studies about the risk of different treatment drugs and other risk factors on the development of CMV disease in SLE are lacking. These studies will be useful for establishing guidelines on the institution of prophylaxis or pre-emptive treatment of CMV infection in SLE patients. Protocols for screening and prevention in this population should be implemented to account for this emerging problem. Given the rising prevalence of CMV infection in the past few years, the authors recommend that patients recently diagnosed with SLE while taking high doses of corticosteroids, which appears to be a risk factor for CMV reactivation, should be routinely tested for CMV viremia. There should be a low threshold for suspicion, hence treatment should be started as soon as possible given the high morbidity and mortality in severe cases.

Stroke and HIV-associated neurological complications: A retrospective nationwide study.

There is an increased risk of stroke and other neurological complications in human immunodeficiency virus (HIV) infected patients with no large population-based studies in the literature. We aim to evaluate the prevalence of stroke, HIV-associated neurological complications, and identify risk factors associated with poor outcomes of stroke among HIV admissions in the United States. In the nationwide inpatient sample with adult HIV hospitalizations, patients with primary cerebrovascular disease (CeVDs) and HIV-associated neurological complications were identified by ICD-9-CM codes. We performed a retrospective study with weighted analysis to evaluate the prevalence of stroke and neurological complicationsand outcomes of stroke among HIV patients. We included 1,559,351 HIV admissions from 2003 to 2014, of which 22470 (1.4%) patients had CeVDs (transient ischemic attack [TIA]: 3240 [0.2%], acute ischemic stroke [AIS]: 14895 [0.93%], and hemorrhagic stroke [HS]: 4334 [0.27%]), 7781 (0.49%) had neurosyphilis, 29,925 (1.87%) meningitis, 39,190 (2.45%) cytomegalovirus encephalitis, 4699 (0.29%) toxoplasmosis, 9964 (0.62%) progressive multifocal leukoencephalopathy, and 142,910 (8.94%) epilepsy. There is increased overall prevalence trend for CeVDs (TIA: 0.17%-0.24%; AIS: 0.62%-1.29%; HS: 0.26%-0.31%; pTrend < .0001) from 2003 to 2014. Among HIV admissions, variables associated with AIS were neurosyphilis (odds ratio: 4.38; 95% confidence interval: 3.21-5.97), meningitis (4.87 [4.10-5.79]), and central nervous system tuberculosis (6.72 [3.85-11.71]). Toxoplasmosis [4.27 [2.34-7.76]), meningitis (2.91 [2.09-4.06)], and cytomegalovirus encephalitis (1.62 [1.11-2.37]) were associated with higher odds of HS compared to patients without HS. There was an increasing trend of CeVDs over time among HIV hospitalizations. HIV-associated neurological complications were associated with the risk of stroke, together with increased mortality, morbidity, disability, and discharge to long-term care facilities. Further research would clarify stroke risk factors in HIV patients to mitigate adverse outcomes.

Next-generation sequencing in the diagnosis of viral encephalitis: sensitivity and clinical limitations

Identification of pathogens causing viral encephalitis remains challenging, and in over 50% of cases the etiologic factor remains undetermined. Next-generation sequencing (NGS) based metagenomics has been successfully used to detect novel and rare infections, but its value for routine diagnosis of encephalitis remains unclear. The aim of the present study was to determine the sensitivity of shotgun metagenomic sequencing protocols, which include preamplification, and testing it against cerebrospinal fluid (CSF) samples from encephalitis patients. For sensitivity testing HIV and HBV positive sera were serially diluted in CSF from an uninfected patient. NGS repeatedly detected HIV and HBV sequences present at concentrations from 105 to 102 and from 105 to 10 viral copies/reaction, respectively. However, when the same protocols were applied to RT-PCR/PCR positive CSF samples from 6 patients with enteroviral encephalitis (median viral load 47 copies/ml) and 15 patients with HSV, CMV or VZV encephalitis (median viral load 148 copies/ml), only 7 (28.6%) were identified as positive. In conclusions, while NGS has the advantage of being able to identify a wide range of potential pathogens it seems to be less sensitive compared to the standard amplification-based assays in the diagnosis of encephalitis, where low viral loads are common.

Etiology and molecular-epidemiological characteristics of viral meningo-encephalitis in Zhejiang province, 2002-2018

Objective: To understand the pathogens and molecular-epidemiologic characteristics of viral meningo-encephalitis in Zhejiang province during 2002 to 2018. Methods: All the samples were collected from suspected patients admitted to the hospitals under the monitoring program. Of the total samples, 2 173 were cerebrospinal fluids while the other 455 were stool specimens. Cerebrospinal fluid (CSF) samples were subject to real-time qPCR for the detection of Human enterovirus (HEV), Mumps virus (MuV), Herpes simplex virus (HSV), Cytomegalovirus (CMV) and Japanese encephalitis virus (JEV). Stool sample were subject to real-time qPCR for HEV. ELISA was used to detect the IgM antibodies in CSF, in the 5 kinds of virus mentioned above. VP1 genes from all RNA-positive specimen were amplified, sequenced, for typing and for evolution analysis. Results: 871 (40.1%) of the 2 173 samples were detected as HEV nucleic acid positive during 2002 to 2018. 654 (38.1%) of the 1 718 CSF sample were HEV nucleic acid positive while 217 (47.7%) of the 455 stool sample were HEV nucleic acid positive. Among the total positive nucleic acid sample, 670 of them were VP1 sequence positive, including 5 HEV-A and 665 HEV-B. There were 23 HEV serotypes, including Coxsackievirus (CV) CVA4, CVA6, CVA9, CVA10, CVB1-5, Echovirus (EchoV; E) E3, E4, E6,E7, E9, E11, E14, E16, E18, E21, E25, E30, E33 and EV-71. The top three serotypes went to E30, E6 and CVB5. These three serotypes presented enhanced viral activity in every several years. 795 CSF samples were detected as virus nucleic acid positive, including 374 HEV, 6 MuV, 5 HSV and 5 CMV, from 2012 to 2015 and in 2018. 5 kinds of IgM antibodies were detected simultaneously in 368 CSF samples, including 2 HEV positive, 6 JEV positive and 1 MuV positive for 5 viruses, respectively. Except for EV-71, there were 517 EchoV and 152 CV viruses presented, with the ratio of 3.4∶1. These two kinds of viruses alternately changed for each predominant epidemic strains in every 3-5 years. Based on VP1, results from the phylogenetic tree showed that HEV from Zhejiang province clustered into HEV-A and HEV-B clades respectively. E30 developed both h and i sub-genotypes. Conclusions: HEV-B seemed the main pathogen for viral meningo-encephalitis in Zhejiang province. Ratio of positive detection on EchoV was significantly higher than that on CV. These two kinds of virus alternately presented changing tendency in every several years. Predominant epidemic strains E30, CVB5 and E6 were presenting enhanced viral activity, also in every several years. High correlation was found in both HEV viral activity from the surveillance sites and in time line of the viral meningo-encephalitis outbreaks.

An HIV-infected patient with acute retinal necrosis as immune reconstitution inflammatory syndrome due to varicella-zoster virus.

An HIV-infected patient with acute retinal necrosis as immune reconstitution inflammatory syndrome due to varicella-zoster virus.

ABSENT MRI FINDING OF HERPES SIMPLEX VIRAL EECEPHALITIS IN RENAL TRANSPLANT PATIENT

SESSION TITLE: Tuesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Herpes simplex viral encephalitis (HSVE) is typically associated with a constellation of frontotemporal features and MRI findings showing increased signal intensity in the temporal lobe, with characteristic sparing of the lentiform nuclei. We report a case of HSVE with profound neurological manifestations without MRI findings in an immunosuppressed adult after kidney transplant. CASE PRESENTATION: 58 year old man with history of renal transplant in 2012 presented with profound ataxia, generalized fatigue for 3 days. He was compliant with Tacrolimus and Mycophenolate without any adverse events. On physical exam the patient was afebrile, normotensive with temporal wasting. His neurological, cardiovascular, chest and abdominal examination were benign. CT head was unremarkable. CT abdomen/pelvis/chest showed numerous hepatic cysts, and transplanted kidney. During the hospitalization he had no resolution of symptoms and had a seizure requiring intubation for airway protection. He was empirically started on Vancomycin and Meropenem . MRI head on day 4 was unremarkable. Tacrolimus level was therapeutic. LP was performed and showed lymphocytic pleocytosis CSF and elevated protein with high RBC count 70. The patient was started on ganciclovir for high clinical suspension of HSV or CMV encephalitis. EEG was abnormal with severe diffuse background slowing. After initiation of antiviral therapy pt demonstrated marked clinical improvement. CSF analysis revealed a positive HSV–2 PCR. The patient was successfully extubated and completed a course of oral acyclovir. DISCUSSION: HSVE is a neurological emergency with high morbidity and mortality. It is caused by herpes simplex virus type one (90%), followed by type two (10%). The presentation is usually nonspecific and may include acute febrile illness with headache, progressive altered mental status, hemiparesis, and seizures. In the immunocompetent adult patient, the pattern is quite typical and MRI usually shows bilateral asymmetrical involvement of the limbic system, medial temporal lobes, and inferolateral frontal lobes. The basal ganglia are typically spared. In immunocompromised patients, involvement can be more diffuse, and more likely to involve the brainstem, but normal MRI findings is highly unusual in HSVE. Our case reinforces the importance of consideration of HSVE in the differential of patient's with suggestive clinical features even with absent MRI finding. CONCLUSIONS: As clinicians, our index of suspicion should remain high in patients presenting with the typical features of encephalitis such as fever, headache, confusion, and clouding of consciousness. Although this case was not a classic presentation for HSVE and MRI was unremarkable, neurologic manifestations in an immunosuppressed host should prompt further exploration. The diagnosis of HSVE is usually established from the combination of the clinical and investigative features. Reference #1: Kaya A, Mert A, et al. Herpes simplex virus encephalitis: clinical manifestations, diagnosis and outcome in 106 adult patients. Sili U, J Clin Virol. 2014;60:112–118. Reference #2: Bulakbasi N, Kocaoglu M Central nervous system infections of herpesvirus family. Neuroimaging Clin N Am. 2008;18:53–84. Reference #3: Croll, Benjamin J et al. “MRI diagnosis of herpes simplex encephalitis in an elderly man with nonspecific symptoms” Radiology case reports vol. 12,1 159-160. 22 Dec. 2016, https://doi.org/10.1016/j.radcr.2016.11.021 DISCLOSURES: No relevant relationships by Mona Alipour, source=Web Response no disclosure on file for Farhad Arjomand; no disclosure on file for Louis Gerolemou; No relevant relationships by Nabil Mesiha, source=Web Response No relevant relationships by Jose Orsini, source=Web Response Speaker/Speaker's Bureau relationship with Allergan Please note: $20001 - $100000 Added 03/18/2019 by Joshua Rosenberg, source=Web Response, value=Honoraria No relevant relationships by Sahar Takkouche, source=Web Response